Alloantibody developed in a factor XIII A subunit deficient patient during substitution therapy; characterization of the antibody

K. Pénzes, C. Vezina, Z. Bereczky, E. Katona, M. Kun, L. Muszbek, G. E. Rivard

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Introduction: In factor XIII A subunit (FXIIIA) deficiency, the development of alloantibodies is extremely rare. Only four reports have been published and the antibodies were not characterized. Aim: The aim of this study was to describe the clinical course and the laboratory diagnosis of a FXIII-A deficient patient who developed alloantibodies. Methods: FXIII activity was assessed with an ammonia release assay. FXIII-A, FXIII B subunit (FXIII-B) and the complex plasma FXIII (FXIII-A2B2) antigens were determined by ELISA. The causative mutation was detected by fluorescent DNA sequencing. The binding of alloantibody to FXIII-A2 and FXIII-A2B2 was studied by surface plasmon resonance. The cleavage of FXIII-A by thrombin and Ca2+-induced activation of thrombin-cleaved FXIII were followed by western blotting and activity measurement, respectively. Results: FXIII activity, FXIII-A2B2 and FXIII-A antigens were below the limit of detection in the patient's plasma. The severe FXIII-A deficiency was due to a novel homozygous mutation resulting in early stop codon (c.127C>T, p.Gln42STOP). The alloantibody bound to FXIII-A2 and FXIII-A2B2 with equally high affinity (Kd~10-8). It accelerated the elimination of administered FXIII concentrate from the circulation, interfered with thrombin and Ca2+-induced activation and inhibited FXIII activity. Attempts to eliminate the alloantibody resulted only in transient improvement. Patient developed intracerebral haemorrhage after a minor trauma and died in spite of aggressive replacement therapy with FXIII concentrate. Conclusion: The anti-FXIII-A alloantibody caused an unmanageable bleeding complication. The antibody was of combined subtype which accelerated the elimination of FXIII and exerted a multiple inhibitory effect on FXIII activation/activity.

Original languageEnglish
Pages (from-to)268-275
Number of pages8
JournalHaemophilia
Volume22
Issue number2
DOIs
Publication statusPublished - Mar 1 2016

Fingerprint

Factor XIII
Isoantibodies
Antibodies
Thrombin
varespladib methyl
Therapeutics
Antigens
Mutation
Surface Plasmon Resonance
Terminator Codon
Clinical Laboratory Techniques
Cerebral Hemorrhage
DNA Sequence Analysis
Ammonia
Limit of Detection
Western Blotting
Enzyme-Linked Immunosorbent Assay
Hemorrhage
Wounds and Injuries

Keywords

  • Acquired FXIII deficiency
  • Alloantibody
  • Bleeding diathesis
  • FXIII
  • Inherited FXIII deficiency

ASJC Scopus subject areas

  • Hematology
  • Genetics(clinical)

Cite this

Alloantibody developed in a factor XIII A subunit deficient patient during substitution therapy; characterization of the antibody. / Pénzes, K.; Vezina, C.; Bereczky, Z.; Katona, E.; Kun, M.; Muszbek, L.; Rivard, G. E.

In: Haemophilia, Vol. 22, No. 2, 01.03.2016, p. 268-275.

Research output: Contribution to journalArticle

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abstract = "Introduction: In factor XIII A subunit (FXIIIA) deficiency, the development of alloantibodies is extremely rare. Only four reports have been published and the antibodies were not characterized. Aim: The aim of this study was to describe the clinical course and the laboratory diagnosis of a FXIII-A deficient patient who developed alloantibodies. Methods: FXIII activity was assessed with an ammonia release assay. FXIII-A, FXIII B subunit (FXIII-B) and the complex plasma FXIII (FXIII-A2B2) antigens were determined by ELISA. The causative mutation was detected by fluorescent DNA sequencing. The binding of alloantibody to FXIII-A2 and FXIII-A2B2 was studied by surface plasmon resonance. The cleavage of FXIII-A by thrombin and Ca2+-induced activation of thrombin-cleaved FXIII were followed by western blotting and activity measurement, respectively. Results: FXIII activity, FXIII-A2B2 and FXIII-A antigens were below the limit of detection in the patient's plasma. The severe FXIII-A deficiency was due to a novel homozygous mutation resulting in early stop codon (c.127C>T, p.Gln42STOP). The alloantibody bound to FXIII-A2 and FXIII-A2B2 with equally high affinity (Kd~10-8). It accelerated the elimination of administered FXIII concentrate from the circulation, interfered with thrombin and Ca2+-induced activation and inhibited FXIII activity. Attempts to eliminate the alloantibody resulted only in transient improvement. Patient developed intracerebral haemorrhage after a minor trauma and died in spite of aggressive replacement therapy with FXIII concentrate. Conclusion: The anti-FXIII-A alloantibody caused an unmanageable bleeding complication. The antibody was of combined subtype which accelerated the elimination of FXIII and exerted a multiple inhibitory effect on FXIII activation/activity.",
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T1 - Alloantibody developed in a factor XIII A subunit deficient patient during substitution therapy; characterization of the antibody

AU - Pénzes, K.

AU - Vezina, C.

AU - Bereczky, Z.

AU - Katona, E.

AU - Kun, M.

AU - Muszbek, L.

AU - Rivard, G. E.

PY - 2016/3/1

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N2 - Introduction: In factor XIII A subunit (FXIIIA) deficiency, the development of alloantibodies is extremely rare. Only four reports have been published and the antibodies were not characterized. Aim: The aim of this study was to describe the clinical course and the laboratory diagnosis of a FXIII-A deficient patient who developed alloantibodies. Methods: FXIII activity was assessed with an ammonia release assay. FXIII-A, FXIII B subunit (FXIII-B) and the complex plasma FXIII (FXIII-A2B2) antigens were determined by ELISA. The causative mutation was detected by fluorescent DNA sequencing. The binding of alloantibody to FXIII-A2 and FXIII-A2B2 was studied by surface plasmon resonance. The cleavage of FXIII-A by thrombin and Ca2+-induced activation of thrombin-cleaved FXIII were followed by western blotting and activity measurement, respectively. Results: FXIII activity, FXIII-A2B2 and FXIII-A antigens were below the limit of detection in the patient's plasma. The severe FXIII-A deficiency was due to a novel homozygous mutation resulting in early stop codon (c.127C>T, p.Gln42STOP). The alloantibody bound to FXIII-A2 and FXIII-A2B2 with equally high affinity (Kd~10-8). It accelerated the elimination of administered FXIII concentrate from the circulation, interfered with thrombin and Ca2+-induced activation and inhibited FXIII activity. Attempts to eliminate the alloantibody resulted only in transient improvement. Patient developed intracerebral haemorrhage after a minor trauma and died in spite of aggressive replacement therapy with FXIII concentrate. Conclusion: The anti-FXIII-A alloantibody caused an unmanageable bleeding complication. The antibody was of combined subtype which accelerated the elimination of FXIII and exerted a multiple inhibitory effect on FXIII activation/activity.

AB - Introduction: In factor XIII A subunit (FXIIIA) deficiency, the development of alloantibodies is extremely rare. Only four reports have been published and the antibodies were not characterized. Aim: The aim of this study was to describe the clinical course and the laboratory diagnosis of a FXIII-A deficient patient who developed alloantibodies. Methods: FXIII activity was assessed with an ammonia release assay. FXIII-A, FXIII B subunit (FXIII-B) and the complex plasma FXIII (FXIII-A2B2) antigens were determined by ELISA. The causative mutation was detected by fluorescent DNA sequencing. The binding of alloantibody to FXIII-A2 and FXIII-A2B2 was studied by surface plasmon resonance. The cleavage of FXIII-A by thrombin and Ca2+-induced activation of thrombin-cleaved FXIII were followed by western blotting and activity measurement, respectively. Results: FXIII activity, FXIII-A2B2 and FXIII-A antigens were below the limit of detection in the patient's plasma. The severe FXIII-A deficiency was due to a novel homozygous mutation resulting in early stop codon (c.127C>T, p.Gln42STOP). The alloantibody bound to FXIII-A2 and FXIII-A2B2 with equally high affinity (Kd~10-8). It accelerated the elimination of administered FXIII concentrate from the circulation, interfered with thrombin and Ca2+-induced activation and inhibited FXIII activity. Attempts to eliminate the alloantibody resulted only in transient improvement. Patient developed intracerebral haemorrhage after a minor trauma and died in spite of aggressive replacement therapy with FXIII concentrate. Conclusion: The anti-FXIII-A alloantibody caused an unmanageable bleeding complication. The antibody was of combined subtype which accelerated the elimination of FXIII and exerted a multiple inhibitory effect on FXIII activation/activity.

KW - Acquired FXIII deficiency

KW - Alloantibody

KW - Bleeding diathesis

KW - FXIII

KW - Inherited FXIII deficiency

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